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The efficacy of DNA vaccination is enhanced in mice by targeting the encoded protein to dendritic cells
Godwin Nchinda, … , Klaus Überla, Ralph M. Steinman
Godwin Nchinda, … , Klaus Überla, Ralph M. Steinman
Published March 6, 2008
Citation Information: J Clin Invest. 2008;118(4):1427-1436. https://doi.org/10.1172/JCI34224.
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Research Article Immunology

The efficacy of DNA vaccination is enhanced in mice by targeting the encoded protein to dendritic cells

Abstract

DNA vaccines promote an immune response by providing antigen-encoding DNA to the recipient, but the efficacy of such vaccines needs improving. Many approaches have considerable potential but currently induce relatively weak immune responses despite multiple high doses of DNA vaccine. Here, we asked whether targeting vaccine antigens to DCs would increase the immunity and protection that result from DNA vaccines. To determine this, we generated a DNA vaccine encoding a fusion protein comprised of the vaccine antigen and a single-chain Fv antibody (scFv) specific for the DC-restricted antigen-uptake receptor DEC205. Following vaccination of mice, the vaccine antigen was expressed selectively by DCs, which were required for the increased efficacy of MHC class I and MHC class II antigen presentation relative to a control scFv DNA vaccine. In addition, a DNA vaccine encoding an HIV gag p41–scFv DEC205 fusion protein induced 10-fold higher antibody levels and increased numbers of IFN-γ–producing CD4+ and CD8+ T cells. After a single i.m. injection of the DNA vaccine encoding an HIV gag p41–scFv DEC205 fusion protein, mice were protected from an airway challenge with a recombinant vaccinia virus expressing the HIV gag p41, even with 1% of the dose of nontargeted DNA vaccine. The efficacy of DNA vaccines therefore may be enhanced by inclusion of sequences such as single-chain antibodies to target the antigen to DCs.

Authors

Godwin Nchinda, Janelle Kuroiwa, Margarita Oks, Christine Trumpfheller, Chae Gyu Park, Yaoxing Huang, Drew Hannaman, Sarah J. Schlesinger, Olga Mizenina, Michel C. Nussenzweig, Klaus Überla, Ralph M. Steinman

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Response to Bogen

Submitter: Ralph Steinman | steinma@mail.rockefeller.edu

The Rockefeller University

Published May 6, 2008

Our recent study had the two new goals, as stated in the last paragraph of the Introduction and summarized again in the first paragraph of the Discussion to: 1) prove that dendritic cell (DC) targeting is indeed occurring when one designs a DC targeted vaccine, as documented in Figure 2, and 2) determine if DC targeting can decisively lower the dose of DNA that is required for inducing T cell immunity including protective immunity, as documented in Figures 4 and 5.

These concepts are unique to our paper, and the paper Professor Bogen refers to does not completely address either issue, i.e., to document the cell types that are presenting antigens from the vaccine and to show a reduction in DNA dose. Furthermore, the study they cite targeted MHC II, which is not a marker for specific types of antigen presenting cells.

Enhancement of DNA vaccines

Submitter: Bjarne Bogen | bjarne.bogen@medisin.uio.no

Authors: Agnete B. Fredriksen1, Karoline W. Schjetne1, Keith M. Thompson1, Inger Sandlie2

Agnete B. Fredriksen<sup>1</sup>, Karoline W. Schjetne<sup>1</sup>, Keith M. Thompson<sup>1</sup>, Inger Sandlie<sup>2</sup><p><sup>1</sup>Center for Immune Regulation, Institute of Immunology, and <sup>2</sup>Institute of Molecular Bioscience, University of Oslo

Published April 14, 2008

The paper by Nchinda et al(1) asks “..whether targeting vaccine antigens to DCs would increase the immunity and protection that results from DNA vaccines”. By using scFvDEC205-antigen fusion DNA constructs delivered i.m. with electroporation, the authors clearly demonstrate this to be the case. The authors acknowledge that a number of investigators have previously demonstrated an increased efficiency of DNA vaccines that, as proteins, target molecules commonly expressed on antigen presenting cells. They go on to state that these previous reports “… have yet to prove that enhanced presentation of vaccine antigens by DC is being achieved…”. Establishment of this mechanism is the main focus of the paper. However, this mechanism has been amply demonstrated earlier. Thus, an MHC class II-specific scFv- tumor antigen DNA construct delivered i.m. with electroporation was shown to enhance priming of antigen presenting cells in draining lymph nodes, resulting in activation and proliferation of antigen-specific CD4+ T cells and protection against a tumor challenge(2). Targeting was shown to be essential. Similar results were obtained by using a scFv from an agonistic anti-CD40 mAb(3) and CCL3 chemokine(4) as targeting units. Bivalency and inclusion of foreign sequences increased the efficiency of targeted vaccine proteins (4). Although CD11c+ DC appear to be crucial for the enhanced efficiency of targeted DNA vaccines(1), future studies should further delineate the phenotypic characteristics of relevant antigen presenting cells, and what surface molecules that may be the best targets for induction of the various arms of immunity. It should also be established whether antigen presenting cells are primed with targeted vaccine proteins in muscle or in draining lymph nodes. Targeted recombinant Ig-based vaccines, pioneered in the 1990s, clearly enhance DNA immunization and are likely to yield new and more efficient vaccines for infectious diseases and perhaps also for cancer.

Reference List

    1. Nchinda,G., Kuroiwa,J., Oks,M., Trumpfheller,C., Park,C.G., Huang,Y., Hannaman,D., Schlesinger,S.J., Mizenina,O., Nussenzweig,M.C. et al 2008. The efficacy of DNA vaccination is enhanced in mice by targeting the encoded protein to dendritic cells J Clin. Invest.

    2. Fredriksen,A.B., Sandlie,I., and Bogen,B. 2006. DNA vaccines increase immunogenicity of idiotypic tumor antigen by targeting novel fusion proteins to antigen-presenting cells Mol. Ther. 13:776-785.

    3. Schjetne,K.W., Fredriksen,A.B., and Bogen,B. 2007. Delivery of antigen to CD40 induces protective immune responses against tumors J Immunol 178:4169-4176.

    4. Fredriksen,A.B., and Bogen,B. 2007. Chemokine-idiotype fusion DNA vaccines are potentiated by bivalency and xenogeneic sequences. Blood 110:1797-1805.

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